An estimated 65,000 patients in the US will be diagnosed with kidney cancer in 2012. Metastatic RCC is a lethal disease with few treatments, and most patients survive less than 2 years after diagnosis. RCC is a highly vascular tumor, producing angiogenic and growth factors triggered by over-expression of hypoxia inducible factors (HIFs) with recent studies demonstrating that the HIF2α subunit, specifically, plays a causal role in carcinogenesis and progression. Our preliminary studies have demonstrated a previously unknown concordant activation of NF-κB with increased HIF2α expression in RCC preclinical models and clinical samples, suggesting they are functionally related. The purpose of this proposal is to investigate the hypothesis that activation of the NF-κB/HIF2α axis promotes RCC tumor growth.